Tryptophan-Kynurenine Pathway Activation and Cognition in Virally Suppressed Women With HIV

Abstract

Immune and cognitive dysfunction persists even in virally suppressed women with HIV (VS-WWH). Since inflammation and HIV proteins induce the enzyme IDO (indoleamine 2, 3-dioxygenase), converting tryptophan (T) to kynurenine (K) while producing downstream neurotoxic metabolites, we investigated IDO activation (KT ratio) in relation to cognition in VS-WWH and demographically similar women without HIV (WWoH). 99 VS-WWH on stable antiretroviral therapy and 102 WWoH (median age 52 vs 54 years; 73% vs 74% Black respectively) from the New York and Chicago sites of the Women’s Interagency HIV Study (WIHS) completed a neuropsychological test battery assessing motor function, processing speed, attention/working memory, verbal fluency, verbal learning and memory, and executive function) and had plasma measured for TK metabolites via liquid chromatography-tandem mass spectrometry and monocyte derived (sCD14, sCD163, MCP-1/CCL-2) plus general inflammatory markers (TNF-RII, hsCRP, hsIL-6) via enzyme-linked immunosorbent assays between 2017-20. VS-WWH had a higher KT ratio (P<0.01) and higher sCD14 levels (P<0.05) compared to WWoH. Higher sCD163 was associated with higher KT ratio (R=0.29, P <0.01), and worse fine motor function in VS-WWH; after adjusting for sCD163 and sCD14 in multivariable regressions, higher KT ratio remained significantly associated with impaired fine motor function in VS-WWH only (standardized β=-0.29, P<0.05). IDO activation was not associated with cognition in WWoH. IDO activation (K:T) was associated with worse fine motor control in VS-WWH independent of measured systemic inflammation. Further studies investigating biological mechanisms linking IDO activation to fine motor function among VS-WWH are warranted.